Men who sleep with men are more severely affected by HIV infection than any other group in the US, representing the vast majority of new infections each year. Pre-exposure prophylaxis (PrEP), the only FDA-approved HIV prevention method, is effective in reducing infection only if patients take their medicines as prescribed. Unfortunately, recent experience with orally administered PrEP indicates the majority of patients do not take their medications regularly. In this research program, a nanotechnology-based pharmaceutical foam administered rectally once a week will be developed to prevent the establishment of permanent HIV infection. Anti-HIV drugs will be released from nanoparticles that are absorbed and stay in colonic and rectal tissue for a week treating early viral exposure locally. Two groups of therapeutic agents, suppressive antiretrovirals and TRAP (therapeutic reclamation of apoptotic proficiency) agents, will be investigated in parallel. The proposed research will accomplish its objectives by first formulating rectally administered foams that spread drug- containing nanoparticles throughout the rectum and colon. The program will next develop nanoparticles that are taken up and remain locally for a week in rectal and colonic tissues. For each drug, multiple groups of nanoparticles will be engineered to have different delays and release times in order to achieve effective drug exposure in the tissue for up to a week. Finally, foams containing the engineered nanoparticles will be evaluated preclinically. This new treatment option, known as mucosal PrEP, may drastically reduce drug dosages and frequency of administration resulting in fewer side effects and increased patient compliance.